Cyclophosphamide, an alkylating agent with a broad spectrum of anti-tumor activity is actually a prodrug which, to be activated must be converted by hepatic microsomal enzymes into 4-hydrocyclophosphamide. This compound subsequently undergoes spontaneous decomposition to a variety of biologically active compounds. Because of its requirement for hepatic activation, cyclophosphamide cannot be used for regional therapy.
In contrast, 4-hydroperoxycyclophosphamide (4-HC), a preactivated derivative of cyclophosphamide, exhibits equal toxicity on a molar basis to cells in vitro as 4-hydrocyclophosphamide, the principal cytotoxic metabolite of cyclophosphamide. (Redwood, et al., preceding of the American Association of Cancer Research, Vol. 23, p. 169, 1982.) 4-HC has been shown to be active in vitro against murine leukemia cells (Hilton, Bio. Chem. Pharmacol. Vol. 33, pp. 1867-1872, 1984), human breast cancer cells (Kubota, et al., GANN, Vol. 74, pp. 437-444, 1983). and Burkitt's lymphoma (De Fabritiis, et al., Blood, Vol. 65, pp. 1064-1070, 1985) cell lines. It is active against human cancer cell line MOLT-4 (a T-cell leukemia) at 2.5 uM, a rhabdomyosarcoma cell line at 8 uM, a breast cancer cell line McF-7 at 9.5 uM and the medulloblastoma cell line TE-671 at 12.8 uM (Arndt et al., Cancer Research, Vol. 47, p. 5932, 1985; Friedman et al., Cancer Research, Vol. 46, p. 2827, 1986.) 4-HC is currently used clinically to purge tumor cells from bone marrow prior to autologous marrow transplantation (Korbling, et al., British Journal of Hematology, Vol. 52, pp. 89-96, 1982; and Kizer, et al., Blood, Vol. 65, pp. 1504-1510, 1985).
In addition, it has been shown that direct intrathecal administration of 4-HC can achieve drug concentrations of 100 uM in the cerebrospinal fluid (which would be cytocidal in vitro) without producing toxicity. (Arndt et al., Cancer Research, Vol. 47, pp. 5932-5934, 1987).
Despite these preliminary findings, it has yet to be established whether 4-HC can effectively treat tumors in vivo. There is a distinct need in the art of tumor therapy for agents which can affect the growth of compartmentalized tumors. Such tumors are often aggressive and difficult to treat even after surgery and irradiation.